This program project is designed to investigate the mechanism and role of hyperglycemia and hyperinsulinemia in explaining the excess risk of cardiovascular disease in people with diabetes. The program provides a multidisciplinary and innovative approach to address the biochemical molecular and genetic factors involved in cardiovascular disease in diabetes. One hypothesis is that accelerated lipid pathways including lipoxygenases provide a link between hyperglycemia, oxidative stress and inflammatory vessel wall changes. The other hypothesis is that specific genetic factors associated with hyperinsulinemia play a major role in coronary artery disease development in people with NIDDM. Project 1 will utilize in vitro and in vivo approaches to evaluate the role of LO enzymes in mediating fatty streak development in diabetes. Project 2 will evaluate the role of LO enzymes and novel species of phosphatidic acid mediating cytokine and growth factor action on vascular smooth muscle cells. Project 3 will involve the characterization of a unique swine model of accelerated atherosclerosis in NIDDM. This model shows "humanoid" features including hypertriglyceridemia and vascular calcification. This model will be utilized to evaluate the in vivo relevance of pathways in projects #1 and #2 and determine the effects of insulin and other therapeutic modalities on atherosclerosis development. Project #4 will combine a unique genetic study in Hispanic families in which the proband has NIDDM. Two groups of families will be studied, one with and one without documented coronary disease in order to determine the genetic factors linked to either development of or protection from coronary disease in the presence of insulin resistance. Clearly, each project has its own scientific merit and focus, however, combined there is a much greater likelihood of increasing our understanding of the features leading to diabetic macrovascular disease and a more rapid translation of this information to new pharmacologic or molecular approaches to reduce this major cause of morbidity and mortality in this country.